Metformin and Diabetic Neuropathy: Think B12

Relation

Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B₁₂Deficiency 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 B₁₂Deficiency in patients taking metformin and the relationship between vitamin B₁₂Deficiency and diabetic neuropathy.

Draft

In this cross-sectional study, researchers used a linear regression model to assess variables that correlated with vitamin B₁₂Levels and the correlation between altered vitamin B₁₂levels and the presence of diabetic neuropathy.

Participant

Researchers reviewed the clinical records of endocrinology patients who visited a hospital endocrinology service in Bogota, Colombia, in 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 longer than 3 months. In total, 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 duration of metformin use was 108 months.

Study parameters assessed

Researchers measured vitamin B₁₂concentrations by chemiluminescence immunoassay, and they were screened for diabetic neuropathy using one of the following methods: nerve conduction study clinical records or the Michigan Neuropathy Screening Instrument (MNSI).

Result

Overall, little vitamin B₁₂Mirrors were found in 7.3% (95% CI: 4.0%–12%) of participants. Altered (low and borderline) vitamin B in patients with diabetic neuropathy₁₂64% (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 who took a higher dose of metformin had lower vitamin B levels₁₂(Coefficient: -0.061; CI 95%: -0.09, -0.024).¹

Key insights

Vitamin B₁₂Deficiency is common, particularly in patients with diabetic neuropathy. In this study, an inverse correlation was found between diabetic neuropathy and plasma levels of vitamin B₁₂. Higher doses of metformin and male gender were factors associated with lower vitamin B levels₁₂.

Practice implications

Vitamin B₁₂Deficiency resulting from metformin is well documented. This paper brings us back to an observation first reported in 1969 that the pharmaceutical metformin for diabetics (mostly type 2) may reduce the absorption of vitamin B₁₂. Thus, metformin could create or exacerbate the causes of diabetic neuropathy.

This raises the question of what else could reduce B₁₂status to such a marginal state that metformin interference resulted in deficiency in 7% of participants.

A PubMed survey using the MeSH terms “diabetes AND metformin” returned 95 publications from 1971 on this topic. In 1971, Tomkin pointed out that the lack of B₁₂reversed with discontinuation of metformin.²This observation and recent publications certainly give reason to consider potential B₁₂Deficiency in patients taking metformin, whether for cancer or diabetes, although the main publication under discussion is B₁₂Deficiency in only about 7% of diabetics using metformin.

This low deficiency prevalence implies that the remaining 93% of participants are not close enough to B₁₂Deficiency for the additional blocking of absorption by metformin to make a difference. This raises the question of what else could reduce B₁₂status to such a marginal state that metformin interference resulted in deficiency in 7% of participants.

Celiac disease, which affects the intake of B₁₂in the small intestine, is one such cause of reduced absorption. It seems that this is at least part of the B₁₂deficiency in diabetics. In one study, researchers tested a group of type 2 diabetics for celiac disease with immunoglobulin A (IgA) tissue transaminase antibodies, and 1.45% were positive.³This may be an artificially low value as IgA deficiency is known to manifest in celiac disease and the test would give a false negative result in such cases.

In addition, many physicians, including this reviewer, have observed that unidentified, uncontrolled diabetics may have diabetic peripheral neuropathy. This is the symptom by which some are initially identified. That doesn't mean these diabetics may not have B₁₂deficiency, but that the direct neurotoxicity of hyperglycemia is a direct neurotoxicant and that B₁₂Deficiency may be an additional factor.

In the publication discussed here, the authors state in their conclusion: “The association between diabetic neuropathy and vitamin B₁₂Deficiency is of great concern because diabetics or prediabetic patients diagnosed with diabetic neuropathy may have neuropathy due to vitamin B₁₂Shortage." While this seems true, the paper appears to be dedicated to the idea that B₁₂Deficiency is solely due to metformin, which doesn't seem to be true.

This reviewer believes that physicians should evaluate total intestinal absorption in all of our patients, not just those receiving metformin. Nevertheless, this publication is a timely reminder to B₁₂status in all patients taking metformin and particularly in those presenting with symptoms of neuropathy.

Note: Vitamin B₁₂Values ​​were classified as low if they were below 200 pg/ml, borderline if they were between 200 and 300 pg/ml, and normal if they were above 300 pg/ml.