Comment on “Concomitant use of metformin and proton pump inhibitors increases vitamin B12 deficiency risk in type 2 diabetes”

Dear Editor,

We read with great interest the article by Jung et al. which reported that the concomitant use of metformin and proton pump inhibitor (PPI) is associated with an increased risk of vitamin B12 deficiency in patients with type 2 diabetes mellitus¹. While the study benefits from a robust nationwide database and appropriate use of propensity score matching, we would like to offer several points for consideration.

First, the authors conclude that even short-term (≥2 weeks) concurrent use of metformin and a PPI in patients with type 2 diabetes mellitus is associated with an increased risk of vitamin B12 deficiency, recommending routine monitoring¹. However, this conclusion appears inconsistent with the well-established physiology of vitamin B12 metabolism. Hepatic stores of vitamin B12 are typically sufficient to prevent deficiency for several years, even in the absence of dietary intake². Therefore, a 2-week exposure to a PPI is unlikely to significantly deplete these stores.

Second, based on the data presented, the incidence rate of vitamin B12 deficiency was 14.3 per 1,000 person-years in the metformin monotherapy group and 15.4 per 1,000 person-years in the metformin + PPI group¹. This corresponds to an absolute risk increase (ARI) of 1.1 per 1,000 person-years and a number needed to harm (NNH) of 909. In practical terms, this means that 909 patients would need to be treated with both metformin and PPI for 1 year to result in one additional case of vitamin B12 deficiency. Given the sample size of 5,600 in the metformin + PPI group, this translates to approximately six additional cases per year—suggesting that the clinical significance of this association may be limited.

Third, while subgroup analyses by age and sex were conducted, the adjusted hazard ratios were not statistically significant, and no formal interaction tests were reported¹. Without such analyses (e.g., interaction terms or P-values for interaction), it is not possible to determine whether age or sex modifies the effect of PPI use on vitamin B12 deficiency. We respectfully suggest that the authors consider including formal interaction testing to enhance the interpretability of subgroup findings, as this would not require additional effort.

Finally, given that vitamin B12 deficiency typically develops over several years in the absence of dietary intake, routine screening for vitamin B12 deficiency in all type 2 diabetes mellitus patients using both metformin and PPI may not be necessary. Instead, targeted screening of those type 2 diabetes mellitus patients who use both metformin and PPI for extended durations (e.g., >1 year) may be more appropriate. This approach could help reduce healthcare costs and avoid unnecessary testing, while still identifying patients at meaningful risk—potentially representing one of the most practical contributions of Jung et al.'s study.

This study did not receive external funding.

The authors declare no conflict of interest.

Approval of the research protocol: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.