Metformin-induced B12 Deficiency Linked to Diabetic Neuropathy

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.