Author's reply to the “Comment on ‘Concomitant use of metformin and proton pump inhibitors increases vitamin B12 deficiency risk in type 2 diabetes’”

Dear editor,

We appreciate the thoughtful comments from Liao et al.¹ regarding our study² and are pleased to address the points they raised and to provide clarification on our methodology and interpretation.

First, Liao et al. pointed out the physiological plausibility of the ≥2 weeks use of concurrent metformin and proton pump inhibitor (PPI) use on vitamin B12 deficiency. We would like to clarify that the 2-week threshold was only used to define overlapping PPI use based on previous literature, in order to capture a broad range of concurrent exposure durations³. In fact, in our as-treated analysis, where PPI discontinuation was included as a censoring event, the total person-years for the metformin + PPI group (n = 5,600) was 1589, corresponding to an average follow-up duration of approximately 3.4 months (around 13.6 weeks) per person. This shows that the actual duration of concurrent drug exposure was longer than 2 weeks in most of the patients in our cohort.

Second, although the absolute risk increase observed in our study appears modest as Liao et al. mentioned, the potential public health implications are more substantial when viewed at the population level. In our cohort, 11,761 of 117,727 (approximately 10%) of patients with type 2 diabetes mellitus (T2DM) were exposed to concurrent metformin and PPI (metformin + PPI). Extrapolating this proportion to the total T2DM population in Korea suggests that nearly 530,000 patients may have received metformin + PPI, which would result in an estimated 584 additional cases of vitamin B12 deficiency per year. This projection is not merely speculative, as our findings are based on the National Health Insurance Service—National Sample Cohort (NHIS-NSC), a stratified 2% sample of the entire Korean population.

Third, while the subgroup analyses demonstrated trends consistent with the overall pooled results across age- and sex-based strata, these subgroup analyses were exploratory in nature and not powered to detect statistical interactions. We acknowledge the absence of formal interaction testing as a limitation; however, further analyses were not feasible due to data access restrictions following the approved analysis period.

Lastly, we agree that vitamin B12 screening should be tailored based on individual patient risk factors. Our findings support the interpretation of concomitant metformin and PPI use as one such risk factor to consider, but not as justification for universal testing. Given the known association between vitamin B12 deficiency and the risk of diabetic neuropathy, the American Diabetes Association (ADA) recommends regular vitamin B12 monitoring in patients presenting with symptoms such as anemia or neuropathy, or in those with additional risk factors, including >4 years of metformin use, malabsorption syndromes, or low dietary intake⁴.

The authors declare no conflict of interest.

Approval of the research protocol: The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Sookmyung Women's University (SMWU) (IRB number: SMWU-2204-HR-016). The requirement for informed.

Informed Consent: N/A.

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

This study utilized secondary data sources, specifically the National Health Insurance Service—National Sample Cohort (NHIS-NSC). As the research involved analysis of publicly available data and did not include direct interaction with human subjects, ethical approval was not required. Consequently, there is no applicable approval date or registration number for this study.

Animal Studies: N/A.