Methodological considerations in assessing metformin-associated vitamin B12 deficiency
Loading...
Date
2026
Journal Title
Journal ISSN
Volume Title
Publisher
SageJournals
Abstract
Description
To the Editor
We read the article by Ballal et al (2025) with interest, as it examines the relationship between long-term metformin use and vitamin B12 deficiency in adults with type 2 diabetes. The authors report that patients with deficiency had used metformin for more than 10 years on average, with approximately 17% exhibiting low or borderline serum B12 levels. This study contributes valuable data on vitamin B12 status in an Indian tertiary-care population; however, several methodological limitations affect the interpretation and clinical relevance of the findings.
The main limitation of the study is its cross-sectional design, which prevents determination of temporal or causal relationships between metformin use and vitamin B12 deficiency or neuropathy. Without baseline vitamin B12 levels or longitudinal follow-up, it is unclear whether deficiency developed after metformin exposure. Neuropathy in diabetes is multifactorial, involving glycemic control, vascular changes, comorbidities, and nutritional status; therefore, the observed association may reflect overall disease burden rather than a direct effect of metformin. Randomized controlled trials have shown more robust temporal evidence linking metformin use with declining vitamin B12 levels.
Interpretation is further limited by inadequate control of confounding factors. The study population demonstrated poor glycemic control based on reported HbA1c levels, which is itself a major risk factor for neuropathy and other microvascular complications, yet this was not fully adjusted for in the analysis. In addition, the close relationship between duration of diabetes and duration of metformin use may have introduced confounding. Inclusion of variables such as glycemic control, renal function, dietary intake, and supplement use would have strengthened the analysis.
Dietary assessment was also limited. Although a proportion of participants were classified as vegetarians, no association was found with vitamin B12 levels. However, broad dietary categories may not accurately reflect actual vitamin B12 intake or absorption. A more detailed dietary assessment using validated tools would help distinguish nutritional deficiency from drug-related effects, particularly in populations with diverse dietary patterns.
Another limitation is the classification of vitamin B12 status. The study did not include functional biomarkers such as methylmalonic acid or homocysteine, which are important for confirming clinically significant deficiency. As a result, combining borderline and deficient cases may overestimate the clinical impact of low vitamin B12 levels, especially since neuropathy is more strongly associated with severe deficiency.
The association between vitamin B12 levels and neuropathy should therefore be interpreted cautiously. Given the cross-sectional design and limited adjustment for confounders, it remains unclear whether neuropathy is attributable to vitamin B12 deficiency or to diabetes itself. Previous studies have reported inconsistent findings, and a causal relationship has not yet been established.
While the study has some limitation, it highlights an important and potentially preventable clinical issue. The observed association between long-term metformin use and lower vitamin B12 levels is consistent with previous evidence and supports consideration of monitoring in long-term users. However, further prospective studies with longitudinal follow-up and better control of confounding variables are needed before recommending routine population-wide screening.
We appreciate the authors’ effort to investigate an underrecognized adverse effect of a widely used medication. Future research incorporating longitudinal designs, functional biomarkers, and comprehensive metabolic and nutritional assessment will help clarify whether metformin independently contributes to clinically significant vitamin B12 deficiency and neuropathy.
Keywords
Metformin, Vitamin B12 deficiency
Citation
Halog E. A., Mangaoang R. L., Aban, J. L. (2026). Methodological considerations in assessing Metformin-associated vitamin B12 deficiency. Clinical Medicine Insights: Endocrinology and Diabetes. 19, 1-2. doi.org/10.1177/11795514261473677