Taking the popular type 2 diabetes drug metformin for a prolonged period, and at higher doses, was linked to a higher risk for severe and painful diabetic peripheral neuropathy in a new study published in the journal Scientific Reports.
Researchers designed the study to try to find out if taking metformin is a risk factor for peripheral neuropathy, which is characterized by numbness, tingling or burning in extremities — typically the legs and feet. They also wanted to know, if such a connection existed, what might be responsible for it. The study participants were 150 adults with type 2 diabetes and peripheral neuropathy. Half of them took metformin for at least six months at the beginning of the study, and half them didn’t take metformin but took another oral diabetes drug. The non-metformin group was selected to match the metformin group in both age and gender balance, and both groups had similar diabetes control, diabetes duration and severity of peripheral neuropathy.
The researchers performed a variety of lab tests on participants, as well as a nerve conduction study of the areas affected by peripheral neuropathy. Lab tests looked at participants’ complete blood count, electrolytes, kidney and liver function, thyroid-stimulating hormone, rheumatoid factor (a measure of inflammation), A1C (a measure of long-term blood glucose control), and blood folate (vitamin B9) and vitamin B12 levels.
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Metformin linked to higher levels of neuropathy
The researchers found that metformin users had significantly higher levels of moderate to severe peripheral neuropathy, with an average Toronto Clinical Scoring System (TCSS) score — a measure of neuropathy severity that takes symptoms, reflexes and sensory impairment into account and ranges from 0 to 19 — of 10 in the metformin group and five in the non-metformin group. On the question of whether metformin users have more severe peripheral neuropathy, it wasn’t even close.
The researchers also found several differences in lab tests that might help explain why metformin users had a higher risk of peripheral neuropathy. Metformin users had a significantly lower average levels of vitamin B12 — 222 pmol/L, compared with 471 pmol/L in the non-metformin group. There were also significant differences in blood levels of a couple of chemicals that might contribute to neuropathy, known as homocysteine and methylmalonic acid. A1C levels were only slightly higher in the metformin group — not enough to be statistically significant, and definitely not enough to account for the much higher level of moderate to severe peripheral neuropathy.
The researchers also found a significant relationship between higher doses of metformin and a higher TCSS (neuropathy severity) score, as well as between higher doses of metformin and lower vitamin B12 levels. These dose-dependent relationships strongly suggest that taking metformin, rather than some other unknown factor, is responsible for the higher severity of neuropathy linked to the drug — and that lower vitamin B12 levels may be at least part of the reason for this effect.
“Our results demonstrate that metformin treatment conveys a potential hazard” for vitamin B12 deficiency, the researchers concluded. “Patients on metformin treatment must monitor regularly” for blood levels of vitamin B12, they noted, as well as for methylmalonic acid and homocysteine. If you’re taking metformin, speak with your healthcare provider about having your levels of B12 monitored.