Metformin and Diabetic Neuropathy: Think B12

Reference

Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B₁₂ deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endoc Connect. 2019;8(10):1324-1329.

Objective

This study evaluated the prevalence of vitamin B₁₂ deficiency in patients using metformin and the relationship between vitamin B₁₂ deficiency and diabetic neuropathy.

Design

In this cross-sectional study, researchers used a linear regression model to evaluate variables that correlated with vitamin B₁₂ levels and the correlation between having altered vitamin B₁₂ levels and the presence of diabetic neuropathy.

Participants

Researchers reviewed the clinical records of endocrinology patients who visited a hospital endocrinology service in Bogota, Colombia, during 2017. They identified patients treated with metformin for more than 3 months and retrospectively identified patients diagnosed with diabetes mellitus or prediabetes who were treated with metformin for more than 3 months. Overall, the study included 162 patients (72 men and 90 women), and the average age was 64 years. The average daily dose of metformin was 1,536 mg, and the average time on metformin was 108 months.

Study Parameters Assessed

Researchers measured vitamin B₁₂ levels by chemiluminescence immunoassay, and they evaluated for diabetic neuropathy by using any of the following: clinical records of nerve conduction study or the Michigan Neuropathy Screening Instrument (MNSI).

Outcome

Overall, low vitamin B₁₂ levels were found in 7.3% (95% CI: 4.0%-12%) of participants. In those with diabetic neuropathy, altered (low and borderline) vitamin B₁₂ level was 64% (95% CI: 47%-78%) compared to 17% (95% CI: 10%-26%) in patients without diabetic neuropathy (coefficient: –110.8; CI 95%: –165.8, –59.7). Those taking a higher metformin dose had lower levels of vitamin B₁₂ (coefficient: -0.061; CI 95%: -0.09, -0.024).¹

Key Findings

Vitamin B₁₂ deficiency is highly prevalent, especially in patients with diabetic neuropathy. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B₁₂. Higher doses of metformin and male sex were factors related to lower levels of vitamin B₁₂.

Practice Implications

Vitamin B₁₂ deficiency secondary to metformin use is well documented. This publication returns us to an observation first reported in 1969 that the pharmaceutical metformin for diabetics (largely type 2) can reduce the absorption of vitamin B₁₂. Thus, metformin could create or add to the causes of diabetic neuropathy.

That raises the question of what else might be reducing B₁₂ status to such a marginal state that metformin’s interference led 7% of participants into deficiency.

A survey of PubMed using the MeSH terms “Diabetes AND Metformin” furnished 95 publications dating from 1971 on this topic. In 1971 Tomkin pointed out that the deficiency of B₁₂ reversed with discontinuation of metformin.² This observation and more recent publications certainly provide reason to consider potential B₁₂ deficiency in patients taking metformin whether for cancer or diabetes, even though the main publication under discussion found B₁₂ deficiency in only about 7% of diabetics using metformin.

This low prevalence of deficiency implies that the remaining 93% of participants are not near enough to B₁₂ deficiency for the additional blockage of absorption by metformin to make a difference. That raises the question of what else might be reducing B₁₂ status to such a marginal state that metformin’s interference led 7% of participants into deficiency.

Celiac disease, which affects the absorption of B₁₂ in the small intestine, is one such cause of reduced absorption. It appears that this contributes to at least some of the B₁₂ deficiency in those with diabetes. In one study researchers tested a group of type 2 diabetics for celiac disease using immunoglobulin A (IgA) tissue transaminase antibodies, and 1.45% were positive.³ This may be an artificially low figure, since IgA deficiency is known to manifest in celiac disease, thus the test would show a false negative in such cases.

Further, many physicians, including this reviewer, have observed that unidentified, uncontrolled diabetics can have diabetic peripheral neuropathy. That is the symptom by which some are initially identified. That is not saying that those diabetics may not have B₁₂ deficiency, but that the direct neurotoxicity of hyperglycemia is a direct neurotoxicant, and that B₁₂ deficiency may be an additive factor.

In the publication under review, the authors state in their conclusion, “The association between diabetic neuropathy and vitamin B₁₂ deficiency is of great importance, since diabetic or prediabetic patients diagnosed with diabetic neuropathy may have neuropathy due to vitamin B₁₂ deficiency.” While that seems true, the publication seems devoted to the idea that B₁₂ deficiency is solely due to metformin, which does not seem true.

It is the belief of this reviewer that physicians should be evaluating overall intestinal absorption in all our patients, not just those on metformin. Still, this publication is a timely reminder to be mindful of B₁₂ status in all patients taking metformin and in particular those who display symptoms of neuropathy.

Note: Vitamin B₁₂ levels were classified as low if they were less than 200 pg/mL, borderline if they were between 200 and 300 pg/mL, and normal if they were higher than 300 pg/mL.