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Metformin linked to vitamin B12 deficiency and peripheral neuropathy in diabetes patients

Metformin-related vitamin B12 deficiency might contribute to clinically significant peripheral neuropathy in diabetes patients, new research suggests.

Guidelines from European Association for the Study of Diabetes (EASD) and the American Diabetes Association do mention vitamin B12 deficiency as a risk of metformin treatment for type 2 diabetes, but they don’t make recommendations for screening or supplementation, said Mattijs Out, MD, an internist of vascular medicine at Bethesda Diabetes Research Center, Hoogeveen, the Netherlands, who presented the findings last week at the European Association for the Study of Diabetes 2015 Meeting.

“This is important. The consequences of vitamin B12 deficiency, like neuropathy or mental changes, may be profound. Even more, they may be difficult to diagnose, because they may be ascribed to old age or diabetes itself and may be or become irreversible. On the other hand, vitamin B12 deficiency is relatively easy to diagnose, and treatment is easy, cheap, and effective,” Dr Out commented.

Previous research from Dr Out’s group and others has linked metformin use to vitamin B12 deficiency (<150 pmol/L), raising concern that the drug may be contributing to peripheral neuropathy separate from the effect of the diabetes itself.

In the current study, Dr Out and colleagues examined, for the first time, a very specific biomarker for tissue B12 deficiency, methylmalonic acid (MMA), and examinedthe impact of that on a validated neuropathy score; they found that the overall increase in MMA outweighed the benefit derived from metformin’s glucose-lowering effect.

But during the question-and-answer period, some doctors expressed skepticism, stating that they hadn’t seen very high rates of vitamin B12 deficiency in decades of metformin use.

Session moderator Guntram Schernthaner, MD, professor of medicine at the Medical University of Vienna, Austria, said: “I measure only in suspected cases and have almost never found a relationship.…The data aren’t strong enough in my opinion. I recommend a large database study to investigate how often it’s occurring.”

Dr Schernthaner added, “You can measure vitamin B12 if you suspect deficiency, but the key question is whether you should have routine screening. But before you recommend this, you have to prove it’s a true effect.”

Measuring Metformin’s Opposing Effects: HbA1c vs MMA

Dr Out and colleagues aimed to dissect the two opposite effects of metformin: a reduction in HbA1c, which would be expected to improve neuropathy scores, and an increase in MMA, a marker of B12 depletion leading to worsening of peripheral neuropathy.

Data were from the Hyperinsulinemia: the Outcomes of its Metabolic Effects (HOME) study of 390 insulin-treated patients with type 2 diabetes from three outpatient clinics in the Netherlands, who were randomized to 850-mg metformin or placebo three times daily for a mean of 4.3 years.

The original study, published in 2010, found that long-term treatment with metformin increased the risk of vitamin B12 deficiency by 19% (P < .001), which resulted in 5% greater homocysteine concentrations (P = .09).

The current analysis includes data collected over those 4.3 years from 17 visits in which measurements of HbA1c and of the clinically validated Valk Neuropathy Score (Diabet Med. 1992;9:716-721) were collected and six visits in which MMA was measured.

Using structural equation modeling with adjustment for age and cardiovascular risk factors and accounting for renal clearance of MMA, Dr Out and colleagues determined that after 4.3 years, metformin treatment was associated with a mean increase in MMA of 0.039 µmol/L (P = .001).

Per “gram-year” of metformin (similar to “pack-years” of cigarettes), there was an overall nonsignificant increase in neuropathy score of 0.032 (P = .34).

This reflects metformin’s competing protective effect, Dr Out noted.

However, with the 0.039-µmol/L increase in MMA factored in, the net effect came to a 0.25-point increase in the Valk neuropathy score, he pointed out.

Clinical Implications As of Now?

Dr Out commented, “With over 100 million prescriptions of metformin per year, many patients may be at risk,” adding that clinical options include screening for vitamin B12 deficiency after 4 years of metformin use or simply supplementing all patients, possibly with a combination metformin-vitamin B12 pill.

He added: “I think it’s always a problem when a side effect is doctor-induced. I think there are enough data to suggest supplementation.”

But Dr Schernthaner disagrees. “I would say this isn’t good enough….You need first a large analysis of vitamin B12 to determine the real level [of deficiency].”

The study was sponsored by Altana, Lifescan, Merck-Lipha, Merck Sharpe & Dohme, and Novo Nordisk. Dr Out and Dr Schernthaner have no relevant financial relationships.

Source: European Association for the Study of Diabetes 2015 Meeting; Stockholm, Sweden. Abstract 220, presented September 18, 2015.

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