Vitamin B12 Deficiency Associated with Metformin and Proton Pump Inhibitors and Their Combinations: Results from a Disproportionality and Interaction Analysis

TL;DR

This study finds that combining metformin and proton pump inhibitors may increase the risk of serious vitamin B12 deficiency complications.

Contribution

The study evaluates real-world risk of vitamin B12 deficiency from metformin, PPIs, and their combinations using FDA adverse event data.

Findings

Metformin and PPIs both show positive safety signals for vitamin B12 deficiency.

Combination therapy with metformin and pantoprazole leads to higher hospitalization and life-threatening event rates.

Elderly patients on combination therapy face higher risk of vitamin B12 deficiency complications.

Abstract

Background: Metformin and proton pump inhibitors (PPIs) are independently associated with vitamin B12 deficiency. Despite frequent co-prescription, particularly in diabetics with gastroesophageal disorders, evidence regarding the combined risk of these medications on vitamin B12 deficiency remains limited. This study aimed to evaluate the real-world risk of vitamin B12 deficiency associated with metformin, PPIs, and their combinations using the United States Food and Drug Administration Adverse Event Reporting System (USFDA AERS) database. Methods: We conducted a disproportionality analysis using USFDA AERS data from 2004 to 2024. We assessed whether metformin, PPIs, or their combinations were reported more often than expected with vitamin B12 deficiency and evaluated associated clinical outcomes, such as hospitalization and life-threatening events. Results: Among 29,661,136 reports, 552 met inclusion criteria, with metformin monotherapy accounting for 274 cases. Positive safety signals were detected for both metformin and all PPIs individually. While statistical interaction measures were not conclusive, patients on metformin–pantoprazole combination therapy experienced significantly higher rates of hospitalization and life-threatening events compared to those on pantoprazole alone. Conclusions: These findings suggest that patients receiving metformin and PPIs together, particularly the elderly, may face a higher risk of serious vitamin B12 deficiency-related complications. Clinicians should consider closer monitoring of vitamin B12 levels and supplementation when needed in patients on combination therapy.

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