Long-Term Metformin Use Linked to Vitamin B12 Deficiency and Neuropathy, Study Finds
USA: A recent study published in Diabetes Research and Clinical Practice highlights a significant concern for individuals with type 2 diabetes mellitus (T2DM) who are on long-term metformin therapy. Researchers, led by Aryana Sepassi from the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, report that prolonged metformin use is strongly linked to vitamin B12 deficiency and an increased risk of peripheral neuropathy. The findings highlight the importance of routine vitamin B12 monitoring in patients on extended metformin therapy.
The analysis utilized data from the National Institutes of Health’s All of Us research program, providing a large real-world population sample that included 14,808 adults with T2DM. Among these, 61.7% reported metformin use, with nearly 38% classified as long-term users (≥4 years). Researchers employed a retrospective, observational cross-sectional design and compared vitamin B12 status and neuropathy prevalence between long-term users, short-term users (<4 years), and individuals who did not use metformin.
The key findings of the study were as follows:
- Patients using metformin for four years or more had a 67% higher risk of vitamin B12 deficiency compared with non-users after adjusting for confounding factors.
- The risk of vitamin B12 deficiency was 38% higher in long-term metformin users compared with those using metformin for a shorter period.
- The prevalence of peripheral neuropathy was 39% higher among long-term users compared to those on short-term therapy.
- The difference in neuropathy risk between long-term users and non-users was not statistically significant, but the trend indicated a concerning pattern.
- The risk of vitamin B12 deficiency increased by approximately 3% for each year following the initiation of metformin therapy, suggesting a cumulative effect over time.
The study highlights a complex interplay between the duration of diabetes, metformin exposure, and neuropathy risk. This relationship emphasizes that neuropathic complications may not solely result from hyperglycemia but also from drug-induced nutritional deficiencies. According to the authors, these findings underscore the necessity of integrating vitamin B12 screening into routine care for patients undergoing prolonged metformin treatment, particularly when they present with symptoms of neuropathy.
The authors acknowledged limitations, including the observational design, which prevents establishing causality, and the inability to fully control for factors such as dietary habits, genetic predispositions, coexisting conditions like anemia, and adherence to vitamin B12 supplementation. Additionally, missing medication history data may have influenced the outcomes.
The researchers conclude that as metformin continues to be widely prescribed—even beyond diabetes care—clinicians should remain vigilant about its long-term implications. Regular vitamin B12 monitoring and timely interventions could be critical in preventing neuropathy, distinguishing its underlying causes, and improving quality of life for patients.
Reference:
Sepassi, A., Wang, J., Yankowski, S., Enkoji, A., Okenwa, M., Morello, C. M., & Hurley-Kim, K. (2025). Associations between long-term metformin use, the risk of vitamin B12 deficiency, and neuropathy: An All of Us research Program study. Diabetes Research and Clinical Practice, 228, 112424. https://doi.org/10.1016/j.diabres.2025.112424
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