Proton pump inhibitors and an increased risk of gastric cancer: how much more evidence is needed?

The paper of Abrahami et al. in Gut is one of the most recent additions to the steadily expanding body of evidence supporting an association between long-term proton-pump inhibitor (PPIs) use and gastric cancer (1). In this study, the United Kingdom Clinical Practice Datalink data are used [1990–2018], including 973,281 new users of PPIs and 193,306 new users of H2-receptor antagonists (H2RAs), comparing the risk of gastric cancer head-to-head in an “active-comparator design” taking into account demographics and lifestyle (1). All users were older than 40 years, followed up from 1 year after cohort entry (median 5 years follow-up), and considered continuously exposed (1). Although the risk of gastric cancer was 45% higher among PPI users compared to H2RA users, the absolute risk was reported to be low, with a number-needed-to harm of 2,121 (5 years) or 1,191 (10 years) (1). Yet, considering the high number of (long-term) PPI users worldwide, with annual prevalences up to 10–30% of all adults, this associated risk is far from negligible (2-5).

Several meta-analyses have been published during the recent years regarding the same question, with similar conclusions, that PPI use is associated with an increased risk of gastric cancer (6-11). Additionally, increased risks have been suggested for many more diseases including gastro-intestinal cancers, osteoporosis, fractures, kidney disease and gastro-intestinal infections including Clostridioides infections, and even overall survival (7,12,13). The list of papers suggesting long-term harmful effects of PPI use is growing steadily.

While the majority of the previous papers investigating the gastric-carcinogenic potential of long-term PPIs used non-exposed individuals as comparator, this paper uses H2RA users as reference group (1). This comparator is used to tackle confounding by indication, a common problem in pharmaco-epidemiology studies. Is it the drug or is it the treatment which “causes” the increased risk? The problem with these gastro-intestinal indications for PPI, is that there is basically no one with lasting indications not being treated in the Western world—and that the alternative treatment, H2RA are clearly less popular—with almost a monopoly position of PPIs. Another approach to confounding by indication regarding this question, is looking at specific indications separately (2) or restrict to one or a few indications like those treated for Helicobacter pylori (14,15). Comparing PPI to H2RA head-to-head like in this UK study would not be feasible in Sweden, with 40 times more PPI maintenance users than H2RA users (2).

The reported absolute risk, with a number-needed-to-harm of 2,121 (5 years) or 1,191 (10 years), was described by the authors as low (1). Yet, we did some back-to-envelope calculations, which actually do show worrisome results. Measures of impact do depend on the prevalence of a certain risk or protective factor. In the presented paper, these numbers-needed-to-harm are based on a population of 40 years and older, and including any new (incident) users of PPIs with a follow-up of at least 1 year (maximal 29 years)—yet everyone was considered to remain exposed. Although no sub-analyses based on age were reported, we previously showed large differences in relative risk based on age, with the highest risks in those younger than 40 years [standardised incidence ratio (SIR) =22.8 versus SIR =2.8 among those older than 70 years] (2). But let us assume the risk is equal in all age groups above 18 years.

PPIs are used by up to 10–30% of adults, with approximately 11% maintenance use (accumulated 6 months) in our nationwide studies in Sweden (2-5). According to another paper by Abrahami et al., PPI prevalence in the UK was 14.2% in 2018 (16). To obtain more conservative estimates, let us assume a prevalence of 10% among adults (18 years or older) and that all gastric cancer cases occur in adults. The Abrahami study was based on incident use, yet one prescription during the follow-up period of maximal 29 years was apparently sufficient (implying their incident use was most likely far above this assumed prevalence).

Table 1 shows the proportion of gastric cancer cases estimated to have been “caused” by PPI use, assuming the abovementioned numbers-needed-to-harm, also reporting the incidence in a few selected countries. This shows that approximately 5–10% of all gastric cancers would be caused by PPIs, assuming a causal relationship. We know that several factors are linked to gastric cancer, including Helicobacter pylori, smoking, diet, alcohol, obesity, etc., of which some are also linked to PPI use. According to US data, 1/3 of cardia adenocarcinoma would be caused by smoking and 1/3 by obesity; and 1/10 of non-cardia cancer by smoking—but drug intake was not considered (17). A recent review on environmental risk factors and gastric cancer did not mention drug intake either (18). With the growing body of evidence showing an association between PPI use and gastric cancer—it is essential to assess what this actually means. For the individual patient, it will remain challenging to pinpoint if PPIs were the causal factor, and we should assume a multi-causal origin in most cases. Yet, if we look at the population-level, PPI use should not be ignored in the evaluation of risk factors for gastric cancer—especially since it is a modifiable risk factor.

To conclude, even if the overall balance between short and long-term harms and benefits pleads in favour of PPI for the individual, it may be important to reconsider how we use PPIs, and particularly avoid long-term use if possible (19). A treatment of up to 4–8 weeks should be sufficient for most common indications of PPIs including gastro-oesophageal reflux, yet deprescribing is challenging (20). It is not known if there is a safe dose and duration for PPI use considering the risk of gastric cancer use since this may depend on the individual characteristics of the patient. Previous studies have used different definitions of PPI-use, like the Abrahami paper considering incident use of one prescription or more during the study period (1); while we used 6 months accumulated use in our Swedish studies (2). It can however be presumed that longer durations would lead to a higher risk of cancer, as continued exposure will also hinder a restoration to healthier gastrointestinal exposure (21,22).

We should also acknowledge our lack of knowledge and understanding on long-term side-effects of any maintenance therapy, not only PPIs. It has been reported that 25% to 70% of long-term PPI use lacks a clear medical indication, so over-prescription of PPIs does occur (23,24). The costs of inappropriate use of PPIs are also alarmingly high, for the patient and society (25).

Acknowledgments

Funding: This work was supported by the Swedish Research Council (No. 2020-01058 to NB).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-22-57/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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