June 3, 2020

Metformin and Diabetic Neuropathy: Think B12

Results from a cross-sectional study
Metformin, along with other factors such as celiac disease, may contribute to vitamin B12 deficiency in diabetics.


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.


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


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.


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).


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.

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  1. Berchtold P, Bolli P, Arbenz U, Keiser G. [Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides)] [article in German]. Diabetologia. 1969;5(6):405-412.
  2. Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971;2(5763):685-687.
  3. Kizilgul M, Ozcelik O, Beysel S, et al. Screening for celiac disease in poorly controlled type 2 diabetes mellitus: worth it or not? BMC Endocr Disord. 2017;17(1):62.