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Strong Evidence That Long-Term Proton Pump Inhibitor Use Increases Colorectal Cancer Risk

Douglas K. Rex, MD, MASGE, reviewing Abrahami D, et al. Gut 2021 Jul 1.

Data vary regarding whether hypergastrinemia and proton pump inhibitor (PPI) use increase adenoma progression and risk of colorectal cancer (CRC). 

The current study from the UK is a population-based cohort study comparing CRC risk in PPI initiators versus histamine-2 receptor antagonist (H2RA) initiators. Strengths of the study include that it is the largest-sized and lengthiest followed-up study to date, it has an active comparator, and it excluded prevalent users.

The study comprised 1.3 million PPI and 292,387 H2RA initiators. Overall, PPI use was not associated with CRC. However, CRC risk appeared when the duration of use and cumulative doses increased. The hazard ratios were 1.60 with ≥4 years cumulative duration and 1.58 with ≥29,200 mg omeprazole dose equivalents.

The number needed to harm was 5343 and 792 for 5 years and 10 years of follow-up, respectively.

Douglas K. Rex, MD, FASGE


We have seen a number of risks of many types attributed to PPIs, many of which have not been confirmed in subsequent and higher quality studies. These data, however, suggest that CRC risk with long-term PPI therapy may be real, though the absolute risk is very low. Pending further study, the authors support the common recommendation to limit the duration and dose of PPI therapy when feasible.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.


Abrahami D, McDonald EG, Schnitzer ME, Barkun AN, Suissa S, Azoulay L. Proton pump inhibitors and risk of colorectal cancer. Gut 2021 Jul 1. (Epub ahead of print) (

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